HIF-1α protects cigarette-induced airway epithelial cell apoptosis in COPD by activating REDD1

Airway epithelial apoptosis is a key in the development and progression of COPD, but the mechanism remains unclear. HIF-1α is a major regulatory factor for maintaining cellular redox homeostasis in the body, promoting cellular adaptive responses in hypoxic conditions and regulating cellular metabolism, immune inflammation, cell proliferation, and cell apoptosis. It is worth exploring whether and how HIF-1α regulates airway epithelial apoptosis in COPD. Here, apoptosis was evaluated by flow cytometry, TUNEL staining, measuring expression of pro-apoptotic proteins including Bcl-2-associated X protein (Bax) and cleaved Caspase-3, and anti-apoptotic protein Bcl-2 in the human bronchial epithelial cell line (BEAS-2B) in vitro. The results revealed that HIF-1α knockdown significantly amplified cigarette-induced apoptosis. Analogously, cigarette exposure induced a significant increase of REDD1, a downstream effector of HIF-1α. Noteworthy, REDD1 overexpression prevented the amplified effects of HIF-1α knockdown on CSE-induced apoptosis. In in vivo study, we established the chronic obstructive pulmonary disease (COPD) model in HIF-1α heterozygous knockdown mice (HIF-1α^+/-). It was found that HIF-1α knockdown significantly enhanced cigarette-induced apoptosis in murine airway epithelial cells. In conclusion, our study demonstrated that HIF-1a/REDD1 plays a protective role through inhibition of airway epithelium apoptosis in cigarette-induced COPD.